Processes and intermediates in the preparation of C5aR antagonists

ABSTRACT

Intermediates and methods are provided for the preparation of selected C5aR antagonist compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/706,296 filed Dec. 6, 2019 which is continuation of Ser. No.16/360,195 filed Mar. 21, 2019 (now U.S. Pat. No. 10,532,982), which isa continuation of U.S. patent application Ser. No. 15/659,468 filed Jul.25, 2017 (now U.S. Pat. No. 10,266,492), which is a divisional of U.S.patent application Ser. No. 14/867,669 filed Sep. 28, 2015 (now U.S.Pat. No. 9,745,268), which application claims the benefit of priority toU.S. Provisional Application Ser. No. 62/057,107, filed Sep. 29, 2014,each of which is incorporated herein by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

The complement system plays a central role in the clearance of immunecomplexes and in immune responses to infectious agents, foreignantigens, virus infected cells and tumor cells. Inappropriate orexcessive activation of the complement system can lead to harmful, andeven potentially life-threatening consequences due to severeinflammation and resulting tissue destruction. These consequences areclinically manifested in various disorders including septic shock;myocardial, as well as, intestinal ischemia/reperfusion injury; graftrejection; organ failure; nephritis; pathological inflammation; andautoimmune diseases.

The activation of the complement pathway generates biologically activefragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxinsand C5b-9 membrane attack complexes (MAC), all which mediateinflammatory responses by affecting leukocyte chemotaxis; activatingmacrophages, neutrophils, platelets, mast cells and endothelial cells;and increasing vascular permeability, cytolysis and tissue injury.

Complement C5a is one of the most potent proinflammatory mediators ofthe complement system. (The anaphylactic C5a peptide is 100 times morepotent, on a molar basis, in eliciting inflammatory responses than C3a.)C5a is the activated form of C5 (190 kD, molecular weight). C5a ispresent in human serum at approximately 80 μg/ml (Kohler, P. F. et al.,J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptidechains, α and β, with approximate molecular weights of 115 kD and 75 kD,respectively (Tack, B. F. et al., Biochemistry 18: 1490-1497 (1979)).Biosynthesized as a single-chain promolecule, C5 is enzymaticallycleaved into a two-chain structure during processing and secretion.After cleavage, the two chains are held together by at least onedisulphide bond as well as noncovalent interactions (Ooi, Y. M. et al.,J. Immunol. 124: 2494-2498(1980)).

C5 is cleaved into the C5a and C5b fragments during activation of thecomplement pathways. The convertase enzymes responsible for C5activation are multi-subunit complexes of C4b, C2a, and C3b for theclassical pathway and of (C3b)2, Bb, and P for the alternative pathway(Goldlust, M. B. et al., J. Immunol. 113: 998-1007 (1974); Schreiber, R.D. et al, Proc. Natl. Acad. Sci. 75: 3948-3952 (1978)). C5 is activatedby cleavage at position 74-75 (Arg-Leu) in the α-chain. Afteractivation, the 11.2 kD, 74 amino acid peptide C5a from theamino-terminus portion of the α-chain is released. Both C5a and C3a arepotent stimulators of neutrophils and monocytes (Schindler, R. et al.,Blood 76: 1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol.138: 794-700 (1987); Cavaillon, J. M. et al., Eur. J Immunol. 20:253-257 (1990)).

In addition to its anaphylatoxic properties, C5a induces chemotacticmigration of neutrophils (Ward, P. A. et al., J. Immunol. 102: 93-99(1969)), eosinophils (Kay, A. B. et al., Immunol. 24: 969-976 (1973)),basophils (Lett-Brown, M. A. et al., J. Immunol. 117: 246-252 1976)),and monocytes (Snyderman, R. et al., Proc. Soc. Exp. Biol. Med. 138:387-390 1971)).

The anaphylactic and chemotactic effects of C5a are believed to bemediated through its interaction with the C5a receptor. The human C5areceptor (C5aR) is a 52 kD membrane bound G protein-coupled receptor,and is expressed on neutrophils, monocytes, basophils, eosinophils,hepatocytes, lung smooth muscle and endothelial cells, and renalglomerular tissues (Van-Epps, D. E. et al., J. Immunol. 132: 2862-2867(1984); Haviland, D. L. et al., J. Immunol. 154:1861-1869 (1995);Wetsel, R. A., Immunol. Leff. 44: 183-187 (1995); Buchner, R. R. et al.,J. Immunol. 155: 308-315 (1995); Chenoweth, D. E. et al., Proc. Natl.Acad. Sci. 75: 3943-3947 (1978); Zwirner, J. et al., Mol. Immunol.36:877-884 (1999)). The ligand-binding site of C5aR is complex andconsists of at least two physically separable binding domains. One bindsthe C5a amino terminus (amino acids 1-20) and disulfide-linked core(amino acids 21-61), while the second binds the C5a carboxy-terminal end(amino acids 62-74) (Wetsel, R. A., Curr. Opin. Immunol. 7: 48-53(1995)).

Only recently have non-peptide based C5a receptor antagonists beendescribed in the literature (e.g., Sumichika, H., et al., J. Biol. Chem.(2002), 277, 49403-49407). Non-peptide based C5a receptor antagonisthave been reported as being effective for treating endotoxic shock inrats (Stracham, A. J., et al., J. of Immunol. (2000), 164(12):6560-6565); and for treating IBD in a rat model (Woodruff, T. M., etal., J of Immunol., 2003, 171: 5514-5520). Non-peptide based C5areceptor modulators also have been described in the patent literature byNeurogen Corporation, (e.g., WO2004/043925, WO2004/018460,WO2005/007087, WO03/082826, WO03/08828, WO02/49993, WO03/084524); DompeS. P. A. (WO02/029187); and The University of Queenland (WO2004/100975).

More recently, compounds having activity as C5aR antagonists have beenidentified and described in U.S. Pat. No. 8,445,515 B2. In general, thecompounds are represented by formula A, while selected embodiments aredescribed as having formula B:

Selected compounds described therein are particularly active whenresolved to their (2R,3S) isomers and are provided as:

The preparation of compound IA has been provided as shown in FIG. 4 ,and involves a lengthy synthesis including a classical resolution ofisomers (see, for example, the conversion of 6 to 7).

There exists a need in the art for more efficient methods of preparationof compounds IA, IB and IC. The present disclosure provides suchmethods, as well as intermediates in the synthetic pathways.

BRIEF SUMMARY OF THE INVENTION

In one aspect, provided herein is a compound useful in the preparationof several C5aR antagonists, having the formula (i-3):

wherein R is selected from H, C₁₋₈ alkyl, aryl and aryl-C₁₋₄ alkyl, or asalt thereof, which is substantially free of enantiomeric ordiastereomeric impurities (the (2R,3R), (2S,3R) and (2S,3S) isomers).

In another aspect, provided herein is a compound useful in thepreparation of several C5aR antagonists, the compound having the formula(ii-4):

or a salt thereof, wherein R¹ is Cl or CF₃, and wherein the compound issubstantially free of enantiomeric or diastereomeric impurities (thecorresponding (2R,3R), (2S,3R) and (2S,3S) isomers).

In yet another aspect, provided herein is a method of preparing acompound having formula (I):

or a salt thereof, wherein R¹ is Cl or CF₃; R² is F or Cl; and R³ is Hor CH₃; and wherein said compound of formula (I) is substantially freeof enantiomeric or diastereomeric impurities, the method comprising:(a) contacting a compound having the formula (i-3):

wherein R is selected from C₁₋₈ alkyl, aryl and aryl-C₁₋₄ alkyl, whichis substantially free of enantiomeric or diastereomeric impurities, or asalt thereof, with a compound having the formula:

wherein LG is a leaving group; under conditions sufficient to form acompound of formula (i-4):

and(b) converting the compound of formula (i-4) to said compound of formula(I) wherein said compound of formula (I) is substantially free ofenantiomeric or diastereomeric impurities.

In still another aspect, provided herein is another method of preparinga compound having formula (I):

or a salt thereof, wherein R¹ is Cl or CF₃; R² is F or Cl; and R³ is Hor CH₃; and wherein the compound of formula (I) is substantially free ofenantiomeric or diastereomeric impurities, the method comprising:(a) contacting a compound having the formula (ii-4):

or a salt thereof, said compound being substantially free ofenantiomeric or diastereomeric impurities, with cyclopentanone and areducing agent under conditions sufficient to form a compound having theformula (ii-5):

and(b) contacting said compound of formula (ii-5) with a compound havingthe formula:

wherein LG is a leaving group; under conditions sufficient to form acompound of formula (I) which is substantially free of enantiomeric ordiastereomeric impurities.

Still other processes are provided as described below having two, three,or four or more synthetic transformations resulting in the preparationof compounds IA, IB and/or IC, or their pharmaceutically acceptablesalts.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a scheme generally illustrating the steps useful inpreparation compounds IA, IB and IC, utilizing a hydrogenation step toset the (2R,3 S) stereochemistry, followed by a reductive amination ofcyclopentanone, benzoylation of the piperidine nitrogen, and addition ofan aniline to form the C3 amide.

FIG. 2 provides a scheme in which the C3 amide formation (final step ofScheme 1) is carried out via conversion of a C3 ester to a C3 carboxylicacid—which upon treatment with a suitable aniline can provide compoundssuch as IA, IB and IC.

FIG. 3 provides a scheme in which the C3 amide is constructed at anearlier stage of synthesis, followed by steps in which hydrogenation isused to set the (2R,3S) stereochemistry, followed by a reductiveamination of cyclopentanone, and concluding with benzoylation of thepiperidine nitrogen to provide compounds such as IA, IB and IC.

FIG. 4 provides a scheme for the preparation of IA as described in U.S.Pat. No. 8,445,515 B2, utilizing a classical resolution step to preparecompound 7 having (2R,3S) stereochemistry.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of such unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl. Substituents for the above noted aryl ringsystems are selected from the group of acceptable substituents describedbelow.

The term “arylalkyl” or “aryl-C₁₋₄ alkyl” is meant to include thoseradicals in which an aryl group is attached to an alkyl group (e.g.,benzyl, phenethyl, and the like).

The above terms (e.g., “alkyl,” and “aryl”), in some embodiments, willrecite both substituted and unsubstituted forms of the indicatedradical. Preferred substituents for each type of radical are providedbelow.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be avariety of groups selected from: -halogen, —OR′, —NR′R″, —SR′,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstitutedaryl, aryl substituted with 1-3 halogens, unsubstituted C₁₋₈ alkyl, C₁₋₈alkoxy or C₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include 1-pyrrolidinyland 4-morpholinyl.

Similarly, substituents for the aryl groups are varied and are generallyselected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂,—CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl. Other suitablesubstituents include each of the above aryl substituents attached to aring atom by an alkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, a wavy line, “

”, that intersects a single, double or triple bond in any chemicalstructure depicted herein, represent the point attachment of the single,double, or triple bond to the remainder of the molecule.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

“Contacting” refers to the process of bringing into contact at least twodistinct species such that they can react. It should be appreciated,however, the resulting reaction product can be produced directly from areaction between the added reagents or from an intermediate from one ormore of the added reagents which can be produced in the reactionmixture.

The term “under conditions sufficient to” refers to the selection ofreaction conditions (including solvents or mixtures of solvents,temperature selection including a change in temperature as a reactionprogresses, concentration of reactants, order of addition of reagentsand reactants to a reaction mixture, length of time for reaction, etc.)which can bring about the desired reaction or transformation of onemolecule to another.

“Converting” refers to carrying out a transformation on a compound tochange the compound to a different compound, such as by modifying onefunctional group to another functional group, joining of two moleculesto form a new molecule, or in some instances salt formation. However,‘converting’ can also involve more than one transformation.

“Solvent” refers to a substance, such as a liquid, capable of dissolvinga solute. Solvents can be polar or non-polar, protic or aprotic. Polarsolvents typically have a dielectric constant greater than about 5 or adipole moment above about 1.0, and non-polar solvents have a dielectricconstant below about 5 or a dipole moment below about 1.0. Proticsolvents are characterized by having a proton available for removal,such as by having a hydroxy or carboxy group. Aprotic solvents lack sucha group. Representative polar protic solvents include alcohols(methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid,acetic acid, etc.) and water. Representative polar aprotic solventsinclude dichloromethane, chloroform, tetrahydrofuran, diethyl ether,acetone, ethyl acetate, dimethylformamide, acetonitrile and dimethylsulfoxide. Representative non-polar solvents include alkanes (pentanes,hexanes, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene,toluene, and 1,4-dioxane.

“Reducing agent” refers to an agent capable of reducing an atom from ahigher oxidation state to a lower oxidation state. Reducing agents caninclude, but are not limited to, zinc, iron, Raney nickel, platinum,iridium, rhodium, palladium, sodium sulfide, sodium dithionite, ammoniumsulfide, and hydrogen donors such as lithium aluminum hydride, sodiumborohydride and sodiumtriacetoxyborohydride.

“Leaving group” refers to groups that maintain the bonding electron pairduring heterolytic bond cleavage. For example, a leaving group isreadily displaced during a nucleophilic displacement reaction. Suitableleaving groups include, but are not limited to, chloro, bromo, iodo,hydroxyl, methanesulfonate (or mesylate), trifluoromethanesulfonate(triflate), benzenesulfonate, 4-methylbenzenesulfonate (tosylate),4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, and the carboxylatecomponent of a mixed or symmetrical anhydride. One of skill in the artwill recognize other leaving groups useful in the present invention.

“Substantially free of enantiomeric or diastereomeric impurities” refersto a compound having at least one chiral center that is present as asingle enantiomer or diastereomer in an amount of at least 80% relativeto other enantiomers or diastereomers of the compound. In someembodiments, the term will refer to a compound that is present as asingle enantiomer or diastereomer in an amount of at least 90%, 95%,96%, 97%, 98%, 99%, or 99.5% relative to other enantiomers ordiastereomers of the compound.

“Nitration agent” refers to a reagent capable of adding a nitro group,—NO₂, to a compound. Representative nitration agents include, but arenot limited to, nitric acid.

“Chlorination agent” refers to a reagent capable of adding a chlorogroup, —Cl, to a compound. Representative chlorination agents include,but are not limited to, phosphorous oxychloride, thionyl chloride,oxalyl chloride and sulfuryl chloride.

The term “pharmaceutically acceptable salts” or “salts” is meant toinclude salts of the compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds contain relativelyacidic functionalities, base addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired base, either neat or in a suitable inert solvent.Examples of salts derived from pharmaceutically-acceptable inorganicbases include aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, manganous, potassium, sodium, zinc and thelike. Salts derived from pharmaceutically-acceptable organic basesinclude salts of primary, secondary and tertiary amines, includingsubstituted amines, cyclic amines, naturally-occuring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, andthe like. Also included are salts of amino acids such as arginate andthe like, and salts of organic acids like glucuronic or galactunoricacids and the like (see, for example, Berge, S. M., et al,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66,1-19). Certain specific compounds of the present invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich may be in a co-crystal form. Co-crystals are those complexes ofthe compounds described herein wherein the compound is crystallized inthe presence of a second compound such as an amino acid, a glycol, or alower alcohol.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention, unless otherwise stated. The compounds of the presentinvention may also contain unnatural proportions of atomic isotopes atone or more of the atoms that constitute such compounds. Unnaturalproportions of an isotope may be defined as ranging from the amountfound in nature to an amount consisting of 100% of the atom in question.For example, the compounds may incorporate radioactive isotopes, such asfor example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C), ornon-radioactive isotopes, such as deuterium (²H) or carbon-13 (¹³C).Such isotopic variations can provide additional utilities to thosedescribed elsewhere with this application. For instance, isotopicvariants of the compounds of the invention may find additional utility,including but not limited to, as diagnostic and/or imaging reagents, oras cytotoxic/radiotoxic therapeutic agents. Additionally, isotopicvariants of the compounds of the invention can have alteredpharmacokinetic and pharmacodynamic characteristics which can contributeto enhanced safety, tolerability or efficacy during treatment. Allisotopic variations of the compounds of the present invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe present invention.

“Kilogram scale” refers to a reaction performed where at least one ofthe reagents used is in an amount of at least 1 kilogram.

General

As noted above, provided herein are intermediates and processes usefulin preparing C5aR antagonist compounds that are useful in treatingdiseases or disorders generally characterized as inflammatory diseasesor disorders, cardiovascular or cerebrovascular diseases or disordersand autoimmune diseases or disorders.

Particular intermediates having a (2R, 3 S) configuration can beprepared according to methods herein, and subsequently converted to theC5aR antagonist compounds.

Embodiments of the Invention

C5aR Antagonist Intermediates

In one aspect, provided herein is a compound useful in the preparationof several C5aR antagonists, the compound having the formula (i-3):

wherein R is selected from H, C₁₋₈ alkyl, aryl and aryl-C₁₋₄ alkyl, or asalt thereof. In one group of embodiments, the compound is substantiallyfree of enantiomeric or diastereomeric impurities. In another group ofembodiments, the compound (i-3) is provided as a L-DTTA salt((−)-O,O′-di-p-toluoyl-L-tartaric acid salt); and in some embodimentsthe compound (i-3) is provided as a bis L-DTTA salt.

A compound of formula (i-3) which is substantially free of enantiomericor diastereomeric impurities, refers to the compound which issubstantially free of one or more of the following isomers (or any saltforms thereof):

As provided herein, the total amount of any one of (i-a), (i-b) or (i-c)is typically less than about 5% by weight relative to the combinedweights of (i-3), (i-a), (i-b) and (i-c). More typically, the amount ofany combination of (i-a), (i-b) and/or (i-c) is less than about 5%, lessthan about 4%, less than about 3%, and in some embodiments is less thanabout 2.5, 2.0, 1.5 or 1.0% on a weight basis relative to (i-3).

In another aspect, provided herein is a compound useful in thepreparation of several C5aR antagonists, the compound having the formula(ii-4):

or a salt thereof, wherein R¹ is Cl or CF₃. In one group of embodiments,the compound is substantially free of enantiomeric or diastereomericimpurities. In another group of embodiments, the compound (ii-4) isprovided as a L-DTTA salt ((−)-O,O′-di-p-toluoyl-L-tartaric acid salt);and in some embodiments, compound (ii-4) is provided as a bis L-DTTAsalt.

A compound of formula (ii-4) which is substantially free of enantiomericor diastereomeric impurities, refers to the compound which issubstantially free of one or more of the following isomers (or any saltforms thereof):

As provided herein, the total amount of any one of (ii-a), (ii-b) or(ii-c) is typically less than about 5% by weight relative to thecombined weights of (ii-4), (ii-a), (ii-b) and (ii-c). More typically,the amount of any combination of (ii-a), (ii-b) and/or (ii-c) is lessthan about 5%, less than about 4%, less than about 3%, and in someembodiments is less than about 2.5, 2.0, 1.5 or 1.0% on a weight basisrelative to (ii-4).

Processes for the Preparation of C5aR Antagonists

In another aspect, provided herein is a method of preparing a compoundhaving formula (I):

or a salt thereof, wherein R¹ is Cl or CF₃; R² is F or Cl; and R³ is Hor CH₃; and wherein said compound of formula (I) is substantially freeof enantiomeric or diastereomeric impurities, the method comprising:(a) contacting a compound having the formula (i-3):

wherein R is selected from C₁₋₈ alkyl, aryl and aryl-C₁₋₄ alkyl, or asalt thereof, which is substantially free of enantiomeric ordiastereomeric impurities, with a compound having the formula:

wherein LG is a leaving group; under conditions sufficient to form acompound of formula (i-4):

and(b) converting the compound of formula (i-4) to said compound of formula(I) wherein said compound of formula (I) is substantially free ofenantiomeric or diastereomeric impurities.

Turning first to step (a), in one group of embodiments, a compound offormula (i-3) is provided which is substantially free of isomers (i-a),(i-b) and (i-c). In certain preferred embodiments, compound (i-3) isprovided and is at least 95% pure, more preferably at least 96%, 97% orat least 98% pure, relative to the other isomers. In even furtherpreferred embodiments, compound (i-3) is provided and is at least 99% or99.5% pure, relative to the other isomers.

In step (a), compound (i-3) is contacted with a compound having theformula:

wherein LG is a leaving group. One of skill in the art will appreciatethat a suitable leaving group is one that facilitates participation ofthe compound in the desired amide bond formation. More particularly, LGis a leaving group that facilitates reaction at the carbonyl centerwhich bears LG. In one group of embodiments LG is a halogen. In anothergroup of embodiments, LG is Cl. In yet another group of embodiments, -LGis selected from —OH, —OAc, —O—S(O)₂-(4-tolyl) and —O—S(O)₂methyl. Inyet another group of embodiments, -LG is —OC(O)Ph(R²)(R³)—forming asymmetrical anhydride with the remainder of the molecule. In someembodiments, the contacting is carried out in an organic solvent orsolvent mixture, or an aqueous solvent mixture—for example, a mixture ofwater and an ether such as methyl t-butyl ether (MTBE). In otherembodiments, the solvent mixture is an aqueous THF, dioxane oracetonitrile solvent mixture. In still other embodiments, the contactingis carried out in the presence of a base. Suitable bases includetriethylamine, N,N-diisopropylethylamine, DBU, and N-methyl morpholine,as well as potassium carbonate (K₂CO₃), potassium bicarbonate (KHCO₃),sodium carbonate (Na₂CO₃) or sodium bicarbonate (NaHCO₃). In one groupof embodiments, the contacting is carried out at temperatures of from−20° C. to about 50° C. In another group of embodiments, the contactingis carried out at ambient temperature (about 25° C.±5° C.). After theinitial contacting the reaction can be monitored until complete, whichdepending on the specific conditions (and solvents) used might involve aperiod of from about 20 minutes to about 3 days. Generally, theproduction of compound (i-4) is completed in about 1-2 hours. In someembodiments, compound (i-4) is isolated according to standard protocolssuch as those provided in the Examples below.

Compound (i-4) can then be converted to the compound of formula (I) viaeither direct amidation on the ester (present in (i-4)) or by firstconverting the ester to a carboxylic acid, followed by formation of theamide using a suitable aniline. As provided herein, a suitable anilineis selected from the group consisting of4-methyl-3-(trifluoromethyl)aniline and 3-chloro-4-methylaniline.

For direct amidation, the aniline is generally combined with compound(i-4) in the presence of a metal reagent such as organoaluminum reagentsor aluminum compounds (salts), alkyllithium compounds, Grignardreagents, organozinc reagents or zinc compounds (salts), sodium hydride,or sodium, potassium or lithium HMDS salts. In some embodiments, themetal reagent in an organoaluminum reagent, such as Al(Me)₃ or DABAL-Me₃(a trimethylaluminum complex with DABCO). In some selected embodiments,the metal reagent is Al(Me)₃.

For those embodiments in which the ester form of compound (i-4) isconverted to a carboxylic acid, the hydrolysis can take place utilizingan aqueous solution of an acid such as sulfuric acid. In someembodiments, temperatures above ambient temperature, for example up to100° C. can be used. Coupling of the carboxylic acid form of (i-4) withan aniline, for example, 4-methyl-3-(trifluoromethyl)aniline or3-chloro-4-methylaniline, can take place either via an activated estermethod (using methanesulfonyl chloride with a base such asN,N-diisopropylethylamine) or another coupling reagent such as HATU witha base such as N-methylmorpholine.

In another aspect, provided herein is another method of preparing acompound having formula (I):

or a salt thereof, wherein R¹ is Cl or CF₃; R² is F or Cl; and R³ is Hor CH₃; and wherein the compound of formula (I) is substantially free ofenantiomeric or diastereomeric impurities, the method comprising:(a) contacting a compound having the formula (ii-4):

or a salt thereof, said compound being substantially free ofenantiomeric or diastereomeric impurities, with cyclopentanone and areducing agent under conditions sufficient to form a compound having theformula (ii-5):

and (b) contacting said compound of formula (ii-5) with a compoundhaving the formula:

wherein LG is a leaving group; under conditions sufficient to form acompound of formula (I) which is substantially free of enantiomeric ordiastereomeric impurities

In one group of embodiments, R¹ is CF₃, R² is F; and R³ is CH₃. Inanother group of embodiments, R¹ is CF₃, R² is Cl; and R³ is H. In yetanother group of embodiments, R¹ is Cl, R² is F; and R³ is CH₃.

Turning first to step (a), in one group of embodiments, a compound offormula (ii-4) is provided which is substantially free of isomers(ii-a), (ii-b) and (ii-c). In certain preferred embodiments, compound(ii-4) is provided and is at least 95% pure, more preferably at least96%, 97% or at least 98% pure, relative to the other isomers. In evenfurther preferred embodiments, compound (ii-4) is provided and is atleast 99% or 99.5% pure, relative to the other isomers.

Compound (ii-4) is generally first contacted with cyclopentanone and anacid to facilitate formation of an intermediate imine, which is thenreduced to the corresponding amine using a suitable reducing agent.Examples of suitable reducing agents include hydrogen gas (with apalladium or other metal catalyst), borohydride reagents and aluminumhydride reagents. In one group of embodiments, the reducing agents areborohydride reagents, such as sodium or lithium borohydride, sodiumcyanoborohydride, or sodium triacetoxyborohydride. Conditions for boththe imine formation and subsequent reduction can be varied according toconventional methods. For example, imine formation can be accomplishedin a single solvent, or a solvent mixture (such as dichloromethane andp-dioxane). Similarly, the temperature for the reactions will beselected to reduce the amounts of side products and maintain a goodyield. Generally, such reactions can be carried out at ambienttemperatures for periods of 1-2 hours up to 18 hours, or more.

The compound of formula (ii-5) can be isolated using standard work upconditions for a reductive amination procedure. Such conditions caninclude, for example, neutralizing any acid in the reaction (orcontacting) mixture and separating the compound (ii-5) by extracting themixture with an organic solvent and then removing solvent from theorganic portions. Typically, further purification of compound (ii-5) isnot necessary before initiating step (b).

In step (b), the product of step (a) is contacted with a compound havingthe formula:

wherein LG is a leaving group. As with the earlier method described, oneof skill in the art will appreciate that a suitable leaving group is onethat facilitates participation of the compound in the desired amide bondformation. More particularly, LG is a leaving group that facilitatesreaction at the carbonyl center which bears LG. In one group ofembodiments LG is a halogen. In another group of embodiments, LG is Cl.In yet another group of embodiments, -LG is selected from —OH, —OAc,—O—S(O)₂-(4-tolyl) and —O—S(O)₂methyl. In yet another group ofembodiments, -LG is —OC(O)Ph(R²)(R³)—forming a symmetrical anhydridewith the remainder of the molecule. In some embodiments, the contactingis carried out in an organic solvent or solvent mixture, or an aqueoussolvent mixture—for example, a mixture of water and an ether such asmethyl t-butyl ether (MTBE). In selected embodiments, the solvent is anorganic solvent such as THF or another ether solvent. In still otherembodiments, the contacting is carried out in the presence of a base.Suitable bases include triethylamine, diisopropyl ethyl amine, DBU, andN-methyl morpholine, as well as potassium carbonate (K₂CO₃), potassiumbicarbonate (KHCO₃), sodium carbonate (Na₂CO₃) or sodium bicarbonate(NaHCO₃). In one group of embodiments, the contacting is carried out attemperatures of from −20° C. to about 50° C. In another group ofembodiments, the contacting is carried out at ambient temperature (about25° C.±5° C.). After the initial contacting the reaction can bemonitored until complete, which depending on the specific conditions(and solvents) used might involve a period of from about 20 minutes toabout 3 days. Generally, the production of compound (I) is completed inabout 1-2 hours. In some embodiments, the compound of formula (I) isisolated according to standard protocols such as those provided in theExamples below.

In yet another aspect, provided herein are processes for the preparationof compounds of formula (I), or a pharmaceutically acceptable salt,solvate, hydrate or rotamer thereof, comprising any two, three or fourof the steps (a), (b), (c), (d), (d1) and (d2), which steps can becontiguous in the synthetic scheme or non-contiguous:

(a) reacting an ester (R is alkyl, preferably C₁₋₈ alkyl, or aryl oraryl-C₁₋₄ alkyl) of 3-(4-nitrophenyl)-3-oxo-propanoate (i-1),(R)-(−)-2-phenylglycinol, and acrolein diethyl acetal or an equivalentthereof, to produce compound (i-2);

(b) hydrogenating or reducing and (i-2) to produce an intermediate amineand converting the intermediate to (i-3) with cyclopentanone and areducing agent;

(c) combining (i-3) with either 2-fluoro-6-methylbenzoyl chloride or2-chlorobenzoyl chloride to provide (i-4);

(d) combining (i-4) with 3-chloro-4-methylaniline or3-trifluoromethyl-4-methylaniline under conditions sufficient to providea compound of formula (I).

Optionally, in some embodiments, the transformation provided in step (d)can be conducted in a two-step process, involving:

(d)(1) conversion of the ester (i-4) to a carboxylic acid (i-5):

(d)(2) combining (i-5) with 3-chloro-4-methylaniline or3-trifluoromethyl-4-methylaniline under conditions sufficient to providea compound of formula (I).

In some embodiments, the process of preparing compounds of formula (I)comprises steps (a) and (b). In other embodiments, the process ofpreparing compounds of formula (I) comprises steps (b) and (c). In yetother embodiments, the process of preparing compounds of formula (I)comprises steps (c) and (d). In still other embodiments, the process ofpreparing compounds of formula (I) comprises steps (c) and (d)(1). Inother embodiments, the process of preparing compounds of formula (I)comprises steps (c) and (d)(2). In still other embodiments, the processof preparing compounds of formula (I) comprises steps (b) and (d). Inyet other embodiments, the process of preparing compounds of formula (I)comprises steps (b) and (d1). In other embodiments, the process ofpreparing compounds of formula (I) comprises steps (b) and (d2).

In some embodiments, the process of preparing compounds of formula (I)comprises steps (a) and (c). In other embodiments, the process ofpreparing compounds of formula (I) comprises steps (a) and (d). In yetother embodiments, the process of preparing compounds of formula (I)comprises steps (a) and (d1). In still other embodiments, the process ofpreparing compounds of formula (I) comprises steps (a) and (d)(2).

In other embodiments, the process of preparing compounds of formula (I)comprises at least three of steps (a), (b), (c), and (d), or optionally(d)(1) and (d)(2). In still other embodiments, the process of preparingcompounds of formula (I) comprises steps (a), (b) and (c). In otherembodiments, the process of preparing compounds of formula (I) comprisessteps (a), (b) and (d). In yet other embodiments, the process ofpreparing compounds of formula (I) comprises steps (a), (b) and (d1). Inother embodiments, the process of preparing compounds of formula (I)comprises steps (a), (b) and (d2). In another group of embodiments, theprocess of preparing compounds of formula (I) comprises steps (b), (c)and (d). In yet other embodiments, the process of preparing compounds offormula (I) comprises steps (b), (c) and (d1). In other embodiments, theprocess of preparing compounds of formula (I) comprises steps (b), (c)and (d2).

In yet another related aspect, provided herein are processes for thepreparation of compounds of formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate or rotamer thereof, comprising anytwo, three or four of the steps (a′), (b′), (c′), (d′) and (e′), whichsteps can be contiguous in the overall synthetic pathway, ornon-contiguous:

(a′) reacting an ester (R is alkyl, preferably C₁₋₈ alkyl, aryl oraryl-C₁₋₄ alkyl) of 3-(4-nitrophenyl)-3-oxo-propanoate (i-1, or ii-1,wherein R is alkyl) with 3-chloro-4-methylaniline or3-trifluoromethyl-4-methylaniline under conditions sufficient to providea compound of formula (ii-2);

(b′) reacting (ii-2), (R)-(−)-2-phenylglycinol, and acrolein diethylacetal or an equivalent thereof, to produce compound (ii-3);

(c′) reducing (ii-3) under conditions sufficient to produce anintermediate diamine (ii-4) that is substantially free of enantiomericor diastereomeric impurities;

(d′) converting (ii-4) to (ii-5) with cyclopentanone and a reducingagent; and

(e′) combining (ii-5) with either 2-fluoro-6-methylbenzoyl chloride or2-chlorobenzoyl chloride to provide (I);

In the processes above using any of steps (a), (b), (c), (d), (d1),(d2), (a′), (b′), (c′), (d′), or (e′), one of skill in the art willunderstand that the indicated compounds can be used, in some instances,as a salt, hydrate or solvate form; and that conditions can be selectedthat facilitate the indicated reaction and to increase the yield of thestep's product and/or the purity of the step's product.

In some embodiments, the process of preparing compounds of formula (I)comprises steps (a′) and (b′). In other embodiments, the process ofpreparing compounds of formula (I) comprises steps (b′) and (c′). In yetother embodiments, the process of preparing compounds of formula (I)comprises steps (c′) and (d′). In still other embodiments, the processof preparing compounds of formula (I) comprises steps (d′) and (e′).

In some embodiments, the process of preparing compounds of formula (I)comprises steps (a′) and (c′). In still other embodiments, the processof preparing compounds of formula (I) comprises steps (a′) and (d′). Inyet other embodiments, the process of preparing compounds of formula (I)comprises steps (a′) and (e′).

In other embodiments, the process of preparing compounds of formula (I)comprises steps (b′) and (d′). In other embodiments, the process ofpreparing compounds of formula (I) comprises steps (b′) and (e′). Inother embodiments, the process of preparing compounds of formula (I)comprises steps (c′) and (e′).

In some embodiments, the process of preparing compounds of formula (I)comprises steps (a′), (b′) and (c′). In some embodiments, the process ofpreparing compounds of formula (I) comprises steps (a′), (b′) and (d′).In some embodiments, the process of preparing compounds of formula (I)comprises steps (a′), (b′) and (e′). In some embodiments, the process ofpreparing compounds of formula (I) comprises steps (a′), (c′) and (d′).In some embodiments, the process of preparing compounds of formula (I)comprises steps (a′), (c′) and (e′). In other embodiments, the processof preparing compounds of formula (I) comprises steps (a′), (d′) and(e′). In yet other embodiments, the process of preparing compounds offormula (I) comprises steps (b′), (c′) and (d′). In still otherembodiments, the process of preparing compounds of formula (I) comprisessteps (b′), (c′) and (e′). In still other embodiments, the process ofpreparing compounds of formula (I) comprises steps (c′), (d′) and (e′).

In other embodiments, the process of preparing compounds of formula (I)comprises at least four of steps (a′), (b′), (c′), (d′), and (e′). Inselected embodiments, the process of preparing compounds of formula (I)comprises steps (a′), (b′), (c′) and (d′). In other embodiments, theprocess of preparing compounds of formula (I) comprises steps (a′),(b′), (c′) and (e′). In yet other embodiments, the process of preparingcompounds of formula (I) comprises steps (a′), (b′), (d′) and (e′). Inother embodiments, the process of preparing compounds of formula (I)comprises steps (a′), (c′), (d′) and (e′). In another group ofembodiments, the process of preparing compounds of formula (I) comprisessteps (b′), (c′), (d′) and (e′). In yet other embodiments, the processof preparing compounds of formula (I) comprises steps (a′), (b′), (c′),(d′) and (e′).

The processes provided above and herein, provide cost effective, safe,efficient, and/or readily scaleable processes useful for the large scaleor commercial production of each of IA, IB and IC, or a pharmaceuticallyacceptable salt, solvate, hydrate, or rotamer thereof.

In one embodiment, provided herein are processes for the preparation ofcompounds of formula (I), or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, that are substantially pure. Inone embodiment, provided herein are processes for the preparation ofcompounds of formula (I), or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, that are substantially chemicallypure. In one embodiment, provided herein are processes for thepreparation of compounds of formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, or rotamer thereof, that is suitablefor use in humans, such as for treating, preventing, and/or managingdiseases or conditions, including but not limited to, diseases mediatedby antagonists of the C5a receptor.

In one embodiment, provided herein are processes for the preparation ofcompounds of formula (I), or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, on a scale of greater than 1 gram,greater than 10 gram, greater than 100 gram, greater than 1,000 gram,greater than 10,000 gram, or greater than 100,000 gram.

In one embodiment, provided herein are processes for the preparation ofcompounds of formula (I), or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, in an overall yield of greaterthan about 10%, greater than about 15%, greater than about 20%, greaterthan about 25%, greater than about 30%, greater than about 40%, greaterthan about 50%, greater than about 60%, greater than about 70%, greaterthan about 80%, greater than about 90%, or greater than about 95%,wherein the yield is calculated based on the limiting starting material.

In one embodiment, provided herein are processes for the preparation ofcompounds of formula (I), or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, that is substantially pure. In oneembodiment, the purity of the compounds of formula IA, IB and IC, or apharmaceutically acceptable salt, solvate, hydrate, or rotamer thereof,is greater than about 95% w/w, greater than about 96% w/w, greater thanabout 97% w/w, greater than about 98% w/w, greater than about 99% w/w,greater than about 99.5% w/w, greater than about 99.8% w/w, greater thanabout 99.9% w/w, greater than about 99.95% w/w, greater than about99.98% w/w, or greater than about 99.99% w/w relative to the totalbatch.

In one embodiment, the total impurities in the compounds of formula IA,IB and/or IC, or a pharmaceutically acceptable salt, solvate, hydrate,or rotamer thereof, produced by a process provided herein, is less thanabout 5% w/w, less than about 4% w/w, less than about 3% w/w, less thanabout 2% w/w, less than about 1% w/w, less than about 0.5% w/w, lessthan about 0.2% w/w, less than about 0.1% w/w, less than about 0.05%w/w, less than about 0.02% w/w, less than about 0.01% w/w, less thanabout 0.005% w/w, or less than about 0.001% w/w relative to the totalbatch.

In one embodiment, an individual impurity in the compounds of formula(I), or a pharmaceutically acceptable salt, solvate, hydrate, or rotamerthereof, produced by a process provided herein, is less than about 5%w/w, less than about 2% w/w, less than about 1% w/w, less than about0.9% w/w, less than about 0.8% w/w, less than about 0.7% w/w, less thanabout 0.6% w/w, less than about 0.5% w/w, less than about 0.4% w/w, lessthan about 0.3% w/w, less than about 0.2% w/w, less than about 0.1% w/w,less than about 0.05% w/w, less than about 0.01% w/w, less than about0.005% w/w, less than about 0.001% w/w, less than about 0.0005% w/w, orless than about 0.0001% w/w relative to the total batch.

In one embodiment, the processes provided herein compounds of formula(I), or a pharmaceutically acceptable salt, solvate, hydrate, or rotamerthereof, that is substantially chemically pure. In one embodiment, thechemical purity of the compound of formula IA, IB or IC, or apharmaceutically acceptable salt, solvate, hydrate, or rotamer thereof,is greater than about 95% w/w, greater than about 96% w/w, greater thanabout 97% w/w, greater than about 98% w/w, greater than about 99% w/w,greater than about 99.5% w/w, greater than about 99.8% w/w, greater thanabout 99.9% w/w, greater than about 99.95% w/w, greater than about99.98% w/w, or greater than about 99.99% w/w relative to the totalbatch.

In one embodiment, the purity profile of a reaction mixture or anisolated product of the processes provided herein is analyzed by one ormore analytical method(s), such as, e.g., HPLC (high performance liquidchromatography), GC (gas chromatography), and TLC (thin layerchromatography). In one embodiment, an impurity is detectable by ananalytical method, such as, e.g., HPLC, GC, or TLC. In one embodiment,the impurity or contemplated impurity in the reaction mixture orisolated product of the processes provided herein includes, but is notlimited to, the starting material used in the reaction or any startingmaterial used in the preceding steps.

In some instances, an impurity in an isolated product of the processesprovided herein may be a volatile organic compound, such as, e.g.,methanol, dimethylformamide, dichloromethane, toluene, acetone, methylt-butyl ether, ethanol, or tetrahydrofuran.

In some instances, the weight loss on drying (LOD) of the compound offormula IA, IB or IC, or a pharmaceutically acceptable salt, solvate,hydrate, or rotamer thereof, produced by a process provided herein, isless than about 5% w/w, less than about 2% w/w, less than about 1% w/w,less than about 0.9% w/w, less than about 0.8% w/w, less than about 0.7%w/w, less than about 0.6% w/w, less than about 0.5% w/w, less than about0.4% w/w, less than about 0.3% w/w, less than about 0.2% w/w, less thanabout 0.1% w/w, less than about 0.05% w/w, or less than about 0.01% w/wrelative to the total batch.

In one embodiment, the residue on ignition of the compound of formulaIA, IB or IC, or a pharmaceutically acceptable salt, solvate, hydrate,or rotamer thereof, produced by a process provided herein, is less thanabout 1% w/w, less than about 0.9% w/w, less than about 0.8% w/w, lessthan about 0.7% w/w, less than about 0.6% w/w, less than about 0.5% w/w,less than about 0.4% w/w, less than about 0.3% w/w, less than about 0.2%w/w, less than about 0.1% w/w, less than about 0.05% w/w, or less thanabout 0.01% w/w relative to the total batch.

In one embodiment, the total heavy-metal-based impurity in the compoundof formula IA, IB or IC, or a pharmaceutically acceptable salt, solvate,hydrate, or rotamer thereof, produced by a process provided herein, isless than about 500 ppm (parts per million) w/w, less than about 200 ppmw/w, less than about 100 ppm w/w, less than about 50 ppm w/w, less thanabout 20 ppm w/w, less than about 10 ppm w/w, less than about 5 ppm w/w,less than about 2 ppm w/w, less than about 1 ppm w/w, less than about0.5 ppm w/w, less than about 0.2 ppm w/w, or less than about 0.1 ppm w/wrelative to the total batch.

In one embodiment, provided herein are processes for preparing thecompound of formula IA, IB or IC, or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, that is substantially free of oneor more residual solvents, including but not limited to, methanol,ethanol, dimethylformamide, toluene, dichloromethane, acetone, methylt-butyl ether, and tetrahydrofuran. In one embodiment, the residualsolvent or the contemplated residual solvent is less than about 5,000ppm w/w, less than about 2,000 ppm w/w, less than about 1,000 ppm w/w,less than about 500 ppm w/w, less than about 200 ppm w/w, less thanabout 100 ppm w/w, less than about 50 ppm w/w, less than about 20 ppmw/w, less than about 10 ppm w/w, less than about 5 ppm w/w, less thanabout 2 ppm w/w, less than about 1 ppm w/w, less than about 0.5 ppm w/w,less than about 0.2 ppm w/w, or less than about 0.1 ppm w/w relative tothe total batch. In one embedment, the contemplated residual solvent,such as, e.g., methanol, ethanol, dimethylformamide, toluene,dichloromethane, acetone, methyl t-butyl ether, and tetrahydrofuran,cannot be detected.

In one embodiment, provided herein are processes for preparing thecompound of formula IA, IB or IC, or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, that has a water content of lessthan about 5% w/w, less than about 4% w/w, less than about 3% w/w, lessthan about 2% w/w, less than about 1% w/w, less than about 0.9% w/w,less than about 0.8% w/w, less than about 0.7% w/w, less than about 0.6%w/w, less than about 0.5% w/w, less than about 0.4% w/w, less than about0.3% w/w, less than about 0.2% w/w, or less than about 0.1% w/w relativeto the total batch.

In one embodiment, provided herein are processes for preparing thecompound of formula IA, IB or IC, or a pharmaceutically acceptable salt,solvate, hydrate, or rotamer thereof, that has the appearance of a whiteor off-white solid.

In one embodiment, one or more steps of the processes provided herein iscarried out under GMP (Good Manufacturing Process) conditions. In oneembodiment, one or more steps of the processes provided herein iscarried under non-GMP conditions.

EXAMPLES

Abbreviations used in the examples below have the following meanings:

aq: aqueous; BBr₃: boron tribromide; CH₂Cl₂ or DCM: dichloromethane;CH₃CN: acetonitrile; CH₃OH or MeOH: methanol; DIEA:N,N-diisopropylethylamine; DMF: dimethyl formamide; DMSO: dimethylsulfoxide; equiv. or eq.: equivalents; Et₃N: triethylamine; Et₂O:diethyl ether; EtOH: ethanol; h: hour(s); HATU,O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HCl: hydrogen chloride; H₂O: water; K₂CO₃:potassium carbonate; KHSO₄: potassium bisulfate; MgSO₄: magnesiumsulfate; mL: milliliter; NaCl: sodium chloride; NaH: sodium hydride;NaHCO₃: sodium bicarbonate; NaOEt: sodium ethoxide; NaOH: sodiumhydroxide; NaOMe: sodium methoxide; Na₂SO₄: sodium sulfate; NH₄Cl:ammonium chloride; NMP: N-methyl pyrrolidinonepH: −log [H⁺]; POCl₃: phosphoryl trichloride; PPTS: pyridiniump-toluenesulfonate; RP-HPLC:

reversed phase high pressure liquid chromatography; RT: roomtemperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thinlayer chromatography

Example 1

This example illustrates the preparation of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideby the method provided more generally in FIG. 1 (Scheme 1) using thereagents provided below:

Route 1:

Step 1: An oven-dried 12 L, 3-necked flask equipped with a mechanicalstirrer, condenser, and thermometer was charged with acrolein diethylacetal (1127 g, 8.666 mole, 1.05 equiv.) and warmed up to 40° C. Amixture of solid ethyl 3-(4-nitrophenyl)-3-oxo-propanoate (1956 g, 8.253mole) and (R)-(−)-2-phenylglycinol (>99.5% e.e., 1187 g, 8.666 mole,1.05 equiv.) was added in portions over 40 min. to maintain a stirrablemixture at an internal temperature of approximately 40° C. After allsolids were added, the mixture was stirred at 40° C. for 10 minutes. 4MHCl in dioxane (206.2 mL, 0.825 mole, 10 mol. %) was subsequently addedthrough the condenser within 2 minutes and the internal temperature wasincreased to 70° C. The reaction was stirred for 22 h whereupon LC-MSshowed consumption of starting materials and enamine intermediate. Theheating was turned off and ethanol (6.6 L) was added. The solution wasthen seeded with 4 g of ethyl(3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylateand stirred at room temperature for 18 h. The solid was subsequentlyfiltered off and 0.1 L of ethanol was used to rinse the flask andequipment onto the filter. The isolated solid was then washed threetimes on the filter with ethanol (250 mL each) and dried under vacuum togenerate 1253 g of ethyl(3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylateas a bright yellow solid (38% yield, 98.5% HPLC wt/wt purity, 0.15 wt %of EtOH).

Step 2: 260 g of ethyl(3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate(0.659 mol), 0.66 L of ethanol, and 56 g of palladium catalyst (10%Pd/C, Degussa type E101 NE/W, 50% wet, 21.5 wt. % of powder, 4.0 mol %Pd) were placed in a 2.2 L Parr bottle and purged with nitrogen. Thebottle was mounted on a Parr shaker apparatus and hydrogen was added ata rate to keep the external temperature of the bottle below 30° C. After4 hours, the consumption of hydrogen slowed down. The bottle was thenshaken under 50 psi of hydrogen for 2 hours. 94 mL of glacial aceticacid (1.65 mol, 2.5 equiv.) was subsequently added to the bottle and thebottle was purged three times with hydrogen at 50 psi. The bottle wasthen shaken under 35-55 psi of hydrogen for 48 hours, keeping thetemperature below 30° C. The bottle was removed from the apparatus and55 mL of 12M HCl aq. was added (0.659 mol, 1 equiv.) followed by 87 mLof cyclopentanone (0.989 mol, 1.5 equiv.). The bottle was purged threetimes with hydrogen at 50 psi and then shaken under 50 psi of hydrogenfor 16-20 hours. The mixture was removed from the apparatus and filteredthrough a fritted funnel containing celite (80 g) and then washed threetimes with 0.125 L of ethanol. 54.1 g of anhydrous sodium acetate (0.659mol, 1 equiv.) was added and the mixture was concentrated in vacuo at40-55° C. to remove 0.9 L of the volatile components. 2.0 L ofacetonitrile was added and 2.0 L of volatile components were removed invacuo. The crude material was diluted with 1.0 L of acetonitrile andmechanically stirred at r.t. for 30 minutes. The mixture was filteredthrough Celite (40 g) and the cake was washed with 0.28 L ofacetonitrile. The combined filtrates gave a solution of the crude amineacetate (Solution A, e.e.=78%). Solutions A of two independent runs werecombined for further processing.

In a 12-L 3-neck flask equipped with a mechanical stirrer, internalthermometer, and reflux condenser (—)—O,O′-di-p-toluoyl-L-tartaric acid(1.019 kg, 2.64 mol, 2 equiv.) was dissolved in 5.8 L of acetonitrile.The mixture was heated to 60° C. with stirring, followed by a quickaddition of 1 L of Solution A. The resultant solution was seeded with 4g of the crystalline ethyl(2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate(−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) and stirred at 60° C.for 15 minutes. After 15 minutes at 60° C. the seed bed has formed. Theremaining amount of Solution A was added over a period of 2.5 hours,maintaining an internal temperature at 60° C. When the addition wascomplete, the heat source was turned off and the mixture was stirred for17 hours, reaching a final temperature of 22.5° C. The suspension wasfiltered and the solids were washed with 0.50 L of acetonitrile to rinsethe equipment and transfer all solids onto the filter. The resultant wetsolids were washed on the funnel with 3.0 L of acetonitrile and dried ina vacuum oven at 45° C. for 48 hours to provide 1.005 kg of ethyl(2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate(−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) as an off-white solid(70% yield, contains 1 wt. % of acetonitrile). The enantiomeric ratio ofthe product was 99.4:0.6.

Step 3: In a 5 L 3-necked flask equipped with a mechanical stirrer andan addition funnel, solid anhydrous potassium carbonate (K₂CO₃, 226 g,1.64 mol, 4.1 equiv.) was dissolved in H₂O (0.82 L) and cooled toambient temperature. MTBE (0.82 L) was added, followed by solid ethyl(2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate(−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) (436 g, 0.400 mol). Themixture was vigorously stirred at r.t. for 1 hour, then2-fluoro-6-methylbenzoyl chloride (72.5 g, 0.420 mmol, 1.05 equiv.) inMTBE (0.14 L) was added dropwise over 1 hour. The product startedprecipitating from the reaction before addition of the acid chloride wascompleted. The reaction was vigorously stirred at r.t. for 30 minutesand monitored by LC-MS for the disappearance of starting material. Themixture was subsequently transferred to a 5 L evaporation flask using0.3 L of MTBE to rinse the equipment and remove all solids. The mixturewas concentrated in vacuo to remove the MTBE, then 0.3 L of heptane wasadded and the mixture was evaporated again to leave only the productsuspended in aqueous solution. The flask was removed from the rotavapand water (0.82 L) and heptane (0.82 L) were added. The suspension wasvigorously stirred for 16 hours using a mechanical stirrer. The contentswere then filtered and the solid was washed with water (2×0.42 L) andheptane (0.42 L). The solid was dried in a vacuum oven at 45° C. toprovide 172 g of ethyl(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylateas an off-white powder (95% yield).

Step 4: A 0.5 L 3-necked round-bottom flask was dried overnight in anoven at 200° C. and then cooled under a stream of nitrogen. The flaskwas equipped with a magnetic stir bar, nitrogen inlet, and athermometer. The flask was charged with 30.2 g of ethyl(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate(66.7 mmol), 11.5 mL of 4-methyl-5-trifluoromethylaniline (80 mmol, 1.2equiv.) and 141 mL of dry toluene under an atmosphere of nitrogen.Nitrogen was bubbled through the resultant solution for 10 minutes andthen the solution was warmed to 30° C. The oil bath was removed and 100mL of a 2 M solution of AlMe₃ in toluene (Aldrich, 200 mmol, 3 equiv.)was cannulated into the reaction mixture at a rate maintaining thereaction temperature between 35-40° C., a process that tookapproximately 45 minutes. The temperature of the reaction mixture wasthen increased to 55° C. over a period of 1 hour and the reactionmixture was stirred at 55° C. for 8 hours, whereupon all of the startingester was consumed (monitored by LC-MS). The reaction was subsequentlycooled overnight to ambient temperature and the solution was thencannulated into a mechanically stirred 1 L flask containing a solutionof 67.8 g of sodium potassium tartrate tetrahydrate (240 mmol, 3.6equiv.) in 237 mL of water, pre-cooled to 10° C. in an ice bath. Theaddition process took approximately 30 minutes, during which thereaction mixture self-heated to 57° C. The empty reaction flask wassubsequently rinsed with 20 mL of dry toluene and the solution wascombined with the quench mixture. The mixture was then cooled to r.t.with stirring, 91 mL of ethyl acetate was added, and the mixture wasstirred an additional 15 minutes. The mixture was subsequently filteredthrough a pad of Celite and the filtrate was allowed to separate intotwo layers. The organic layer was then separated and washed with asolution of 5.7 g of sodium potassium tartrate tetrahydrate (20 mmol) in120 mL of water and then with two 120 mL portions of water. The wetorganic solution was concentrated in vacuo to a weight of ˜150 g and asolvent exchange with ethanol was performed maintaining a total volumeof 0.2-0.3 L, until <1 mol. % toluene with respect to ethanol wasobserved by ¹H NMR. The solution was then evaporated at elevatedtemperature to a weight of 223 g and heated to reflux. Mechanicalstirring was initiated and 41 mL of water was added. The resultingsolution was seeded with(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamidecrystals at 60° C. and then slowly cooled to r.t. over 2 hours. Theslurry was subsequently stirred for 18 hours and the solids werefiltered off. The solids were then washed with two 30 mL portions of 7:3ethanol/water and dried in a vacuum oven for 24 hours at 50° C. toafford 31.0 g of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideas off-white crystals (80% yield). Analytical data: HPLC purity:99.59%; >99.8% d.e. and e.e. by HPLC; ICP-OES Pd: <1 ppm; Al: 6 ppm;residual toluene by headspace GC-MS: 15 ppm; microash <0.1%; K—F 0.1%.¹H NMR (400 MHz, TFA-d) δ 7.91 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz,1H), 7.58-6.82 (m, 8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H),3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m,7H), 2.04-1.92 (m, 4H), 1.82-1.69 (m, 7H), MS: (ES) m/z 582 (M+H⁺).

Example 2

This example illustrates the preparation of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideby the general method provided in FIG. 2 (Scheme 2) using the reagentsshown in Route 2:

Route 2:

Step 1: Solid ethyl(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate(316 g, 0.698 mol) was added portionwise to a 12 L flask containingmechanically stirred 2.80 L of 0.44 M H₂SO₄ in water heated to 70° C.0.36 L of additional 0.44 M H₂SO₄ was used to wash the solids down fromthe funnel. The suspension was brought to 95° C. and stirred at thistemperature for 21 hours, whereupon full dissolution has occurred and nomore than 4% of starting material was remaining. The reaction was cooleddown to ambient temperature. To the mixture were added 2.80 L of 1 MNaOH in water over a period of 30 minutes maintaining the temperaturearound 20° C., followed by 1.58 L of MTBE and again 1.40 L of 1M NaOH.The mixture was vigorously stirred for 1 hour until all the solids weredissolved (final pH was 13.1). The layers were separated and the organiclayer was discarded. The aqueous layer was again extracted with 1.58 Lof MTBE. The aqueous layer was concentrated in vacuo to remove excessMTBE. The solution was transferred back to the mechanically stirredflask and the solution was acidified with 1 M H₂SO₄ over 25 minutesuntil a pH of 4.8 was reached (approximately 0.71 L of 1M H₂SO₄) and theresultant mixture was stirred at ambient temperature for 1 h. The slurrywas filtered and the solids were washed with two 2.0 L portions of waterfollowed by 1.0 L of heptane. The solid was dried in a vacuum oven at45° C. to give 279 g of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylicacid as a white solid (94% yield).

Step 2, condition 1: To a 12 L flask containing(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylicacid (277 g, 0.652 mol) in 1.66 L of dichloromethane was added4-methyl-3-(trifluoromethyl)aniline (112 mL, 137 g, 0.782 mol, 1.2equiv.) followed by N,N-diisopropylethylamine (204 mL, 152 g, 1.17 mol,1.8 equiv.). The solution was cooled to 0° C. and methanesulfonylchloride (65.6 mL, 97.1 g, 0.848 mol, 1.3 equiv.) was added dropwise.After stirring for 18 hours at ambient temperatureN,N-diisopropylethylamine (114 mL, 84.2 g, 0.652 mol, 1.0 equiv.) wasadded. The reaction mixture was stirred at ambient temperature for 15minutes and 2.22 L of isopropyl acetate and 0.55 L of DCM were added tothe flask. The solution was washed with 2.22 L of water and then againwith 1.11 L of water. The organic layer was washed twice with 2.22 Lportions of 0.1M sodium hydroxide in water. 139 g of anhydrous sodiumsulfate was added to the organic layer and stirred for 15 minutes. Tothe suspension 544 g of silica gel (230-400 mesh) was added and themixture was stirred for 30 minutes. The suspension was filtered using atall fritted funnel and the silica gel bed was washed on the funnel with2.50 L of isopropyl acetate/DCM (1:1). The combined solution wasconcentrated in vacuo at 40° C. to an approximate weight of 760 g. Theflask was equipped with a mechanical stirrer at which point spontaneouscrystallization commenced. After 15 minutes of stirring 1.14 L ofheptane was added to the suspension over a period of 20 minutes. 16hours of stirring at ambient temperature yielded colorless crystals,which were filtered off and sequentially washed on the funnel with twoportions of heptane (0.76 L and 0.38 L). The solids were dried in avacuum oven for 16 h at 45° C. to afford 289 g of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideas colorless crystals (76% yield, e.e. 98.6%, 1.4 wt. % of isopropylacetate (by ¹H NMR); 98.1% purity by HPLC at 220 nm). ¹H NMR (400 MHz,TFA-d) δ 7.91 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-6.82 (m,8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H),3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m,4H), 1.82-1.69 (m, 7H), MS: (ES) m/z 582 (M+H⁺).

Step 2, condition 2: To a 250 mL flask containing(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylicacid (8.01 g, 18.8 mmol) in 40 mL of isopropyl acetate was added4-methyl-3-(trifluoromethyl)aniline (2.97 mL, 3.62 g, 20.7 mmol, 1.1equiv.) followed by N-methylmorpholine (3.10 mL, 2.85 g, 28.2 mmol, 1.5equiv.) and HATU (9.29 g, 24.4 mol, 1.3 equiv.). After stirring for 44hours at ambient temperature the reaction mixture was diluted with 100mL of isopropyl acetate and 60 mL of water and stirred for 15 minutes.The undissolved solids were filtered off and the aqueous layer wasdiscarded. The organic phase was washed twice with 60 mL of water andthen concentrated in vacuo to a weight of 58 g. The solvent was thenexchanged with ethanol by co-distillation and the solution wasconcentrated in vacuo to a weight of 74 g (0.6 wt. % of isopropylacetate remaining). The mixture was heated to reflux and 14 mL of waterwas added. The resulting solution was seeded with(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamidecrystals at 60° C. and then slowly cooled to r.t. over 2 hours. Theslurry was subsequently stirred for 18 hours and the solids werefiltered off. The solids were then washed with two 8 mL portions of 7:3ethanol/water and dried in a vacuum oven for 24 hours at 50° C. toafford 7.91 g of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideas colorless crystals (72% yield). Analytical data: HPLC purity:99.26%; >99.8% d.e.and e.e. by HPLC. ¹H NMR (400 MHz, TFA-d) δ 7.91 (d,J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-6.82 (m, 8H), 6.75 (t, J=8.6Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H),3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-1.69 (m,7H), MS: (ES) m/z 582 (M+H⁺).

Example 3

This example illustrates the preparation of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideby the general method provided in FIG. 3 (Scheme 3), using the reagentsshown in Route 3:

Route 3:

Step 1: To a 500 mL, 3-necked, round bottom flask equipped with athermometer was added ethyl 3-(4-nitrophenyl)-3-oxo-propanoate (50 g,211 mmol), o-xylene (100 mL) followed by4-methyl-3-(trifluoromethyl)aniline (33.25 mL, 232 mmol) and theresulting reaction mixture was stirred at 130° C. for 6 h (ethanolgenerated during the reaction was removed using a distillation condenseras it was formed). The reaction mixture was cooled to room temperatureand aged overnight. Obtained crystals were collected by filtration,washed with diethyl ether (500 mL), dried under high vacuum to obtainN-[4-methyl-3-(trifluoromethyl)phenyl]-3-(4-nitrophenyl)-3-oxo-propanamide(74.4 g) in 96% yield as bright yellow crystalline solid. ¹H NMR showed˜2:1 mixture of keto-enol tautomers. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61(bs, 1H), 10.48 (s, 1H), 8.37-8.31 (m, 2H), 8.21 (d, J=9 Hz, 1H),8.0-7.95 (m, 2H), 7.65 (dd, J=21.2, 8.2 Hz, 1H), 7.37 (dd, J=13.3, 8.2Hz, 1H), 6.06 (s, 1H), 4.25 (s, 2H), 2.37, 2.36 (2s, 3H); MS: (ES) m/z367 (M+H⁺).

Step 2: A mixture of (R)-(−)-2-phenylglycinol (3.02 g, 22 mmol),N-[4-methyl-3-(trifluoromethyl)phenyl]-3-(4-nitrophenyl)-3-oxo-propanamide(7.32 g, 20 mmol), acrolein diethyl acetal (4 mL, 28.6 mmol) and formicacid (0.8 mL, 20 mmol) in p-dioxane (10 mL) was stirred at 90° C. for 4h. The reaction mixture was cooled to room temperature, diluted withdichloromethane (20 mL), adsorbed on silica gel and purified by columnchromatography (product was eluted with 30% ethyl acetate in hexanes) toobtain(3R)—N—[4-methyl-3-(trifluoromethyl)phenyl]-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxamide(8.4 g) in 80% yield as yellow foam with diastereomeric ratio of ˜3:2.¹H NMR (400 MHz, CDCl₃) δ 7.96-786 (bs, 1H), 7.20-7.15 (m, 3H), 7.15-7.0(m, 6H), 6.9 (dd, J=7.81, 1.57 Hz, 1H), 6.7 (d, J=8.6 Hz, 1H), 6.44 (d,J=29.7 Hz, 1H), 5.26 (dd, J=8.6, 3.5 Hz, 0.6 H), 5.06 (dd, J=9.77, 2.73Hz, 0.4 H), 4.48 (d, J=6.25 Hz, 0.5H), 4.36-4.28 (m, 1H), 4.22-4.17 (m,0.5H), 4.02 (dd, J=8.99, 1.56 Hz, 0.5H), 3.8 (dd, J=8.6, 5.08 Hz, 0.5H),3.2-2.8 (m, 1H), 2.7-2.4 (m, 2H), 2.14 (s, 3H), 1.95-1.85 (m, 1H); MS:(ES) m/z 524 (M+H⁺).

Step 3:(3R)—N—[4-methyl-3-(trifluoromethyl)phenyl]-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxamide(2.1 g, 4 mmol), DMF (12 mL), palladium catalyst (10% Pd/C, Degussa typeE101 NE/W, 50% wet, 800 mg, 45 wt % of powder, 0.36 mmol) and aceticacid (0.6 mL, 10 mmol) were placed in a Parr bottle and agitated underhydrogen gas (60 psi) for 20 hours at ambient temperature. The reactionmixture was passed through a frit to remove palladium catalyst, washedwith methanol (2×20 mL) and evaporated to dryness on rotavapor in vacuoto obtain the crude product. To this crude product was added wthylacetate (30 mL), dichloromethane (60 mL),(−)-O,O′-di-p-toluoyl-L-tartaric acid (L-DTTA, 1.55 g, 4 mmol) and theresulting mixture was aged at room temperature overnight. Obtainedcrystals were collected by filtration, washed with cold ethyl acetate(2×10 mL) and dried under high vacuum to obtain(2R,3S)-2-(4-aminophenyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamideas 1:1 L-DTTA salt (1.32 g) in 43% yield with enantiomeric ratio of 98:2(chiral column: Regis Cell, HPLC system: Agilent 1200 Series ModelG1312A, solvent: 0.1% diethylamine in MeOH, isocratic, flow rate: 1mL/min, ambient temperature, retention time for major isomer: 6.86 min).¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J=6.6 Hz, 4H), 7.88 (d, J=2.35 Hz,1H), 7.5 (dd, J=8.4, 2.34 Hz, 1H), 7.28 (d, J=7.8 Hz, 2H), 7.26 (d,J=8.99 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 5.87 (s,2H), 4.35 (d, J=3.12 Hz, 1H), 3.52-3.58 (m, 1H), 3.06-3.23 (m, 2H), 2.40(s, 9H), 2.18-2.12 (m, 2H), 1.84 (d, J=14.46 Hz, 1H); MS: (ES) m/z 378(M+H⁺).

Step 4: To(2R,3S)-2-(4-aminophenyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide(−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:1) (15.17 g, 19.85 mmol)in dichloromethane (100 mL) was added cyclopentanone (1.93 mL, 21.84mmol), 4 N HCl in p-dioxane (6.31 mL, 25.24 mmol) and acetic acid (3.57mL, 59.55 mmol) followed by sodium triacetoxyborohydride (6.31 g, 29.78mmol) at room temperature and the resulting reaction mixture was stirredat room temperature overnight. Saturated sodium bicarbonate solution(100 mL) was added slowly and the organic layer was separated. Aqueouslayer was further extracted with dichloromethane (2×100 mL) and combinedorganic layers were dried over anhydrous sodium sulfate and concentratedin vacuo to obtain crude(2R,3S)-2-[4-(cyclopentylamino)phenyl]-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide(9.5 g) which was used as such in the next step without furtherpurification. ¹H NMR (400 MHz, CD₃OD) δ 7.71 (d, J=1.96 Hz, 1H), 7.43(dd, J=8.2, 1.95 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.6 Hz,2H), 6.58 (d, J=8.6 Hz, 2H), 3.88 (d, J=3.52 Hz, 1H), 3.69 (q, J=12.1,6.3 Hz, 1H), 3.33-3.35 (m, 1H), 2.88-2.78 (m, 2H), 2.39 (s, 3H),2.16-1.85 (m, 5H), 1.75-1.5 (m, 5H), 1.45-1.35 (m, 2H); MS: (ES) m/z 446(M+H⁺).

Step 5: To a flask containing a solution of sodium bicarbonate (1.9 g,22.62 mmol) in 45 mL of water was added a solution of crude(2R,3S)-2-[4-(cyclopentylamino)phenyl]-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide(5.0 g, 11.23 mmol) in 90 mL of tetrahydrofuran over a period of 10minutes. The resulting mixture was stirred at ambient temperature for 1hour. 2-Fluoro-6-methylbenzoyl chloride (1.73 g, 8.98 mmol) in 5 mL oftetrahydrofuran was added dropwise over 10 minutes. Upon completion ofthe reaction, the undissolved solid was filtered off and the filtratewas concentrated in vacuo. Heptane (50 mL) was added to the remainingaqueous layer and the mixture was vigorously stirred for 16 h at roomtemperature. The contents were filtered and the solid was washed withwater (2×30 mL) followed by heptane (30 mL). The solid was dried underhigh vacuum to obtain crude product (3.68 g) which was dissolved inethanol (22 mL) with gentle heating and then water (4 mL) was added.Obtained brown colored clear solution was cooled to room temperature andstirred overnight. Crystals were collected by filtration, washed withcold ethanol (5 mL), dried under high vacuum to get(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide(1.66 g) in 28% yield for two steps with enantiomeric ratio of 98:2(chiral column: Pirkle Covalent, (S,S) Whelk-O1, 5/100, 25 cm×4.6 mmKromasil, S/N 50404, HPLC system: Agilent 1200 Series Model G1312A,solvent: 15% hexanes in iso-propanol, isocratic, flow rate: 1 mL/min,column temperature: 75° C., retention time of major isomer: 9.9 min). ¹HNMR (400 MHz, TFA-d) δ 7.91 (d, J=8.6 Hz, 1 H), 7.84 (d, J=8.6 Hz, 1H),7.58-6.82 (m, 8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47(m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H),2.04-1.92 (m, 4H), 1.82-.169 (m, 7H), MS: (ES) m/z 582 (M+H⁺).

Example 4

This example illustrates the synthesis of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-chlorophenyl]piperidine-3-carboxamide:

To a 100 mL flask containing(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylicacid (2.71 g, 6.38 mmol) in 20 mL of dichloromethane was added3-chloro-4-methylaniline (0.85 mL, 7.01 mmol, 1.1 equiv.) followed byN-methylmorpholine (1.05 mL, 968 mg, 9.57 mmol, 1.5 equiv.) and HATU(2.91 g, 7.66 mol, 1.2 equiv.). After stirring for 24 hours at ambienttemperature the reaction mixture was concentrated in vacuo, diluted with50 mL of isopropyl acetate and 20 mL of water and stirred for 15minutes. The undissolved solids were filtered off and the aqueous layerwas discarded. The organic phase was washed twice with 20 mL of waterand then concentrated in vacuo to dryness. The solids were evaporatedtwice with 30 mL of ethanol. The resulting residue was then dissolved in22 mL of refluxing ethanol and 4 mL of water was added. The resultingsolution was then refluxed for 15 minutes (until initial seed bed wasformed) and then slowly cooled to r.t. The slurry was subsequentlystirred for 3 hours and the solids were filtered off. The solids werethen washed with 10 mL of 7:3 ethanol/water and dried in a vacuum ovenfor 24 hours at 50° C. to afford 2.95 g of(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-chlorophenyl]piperidine-3-carboxamideas colorless crystals (84% yield).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety for all purposes.

What is claimed is:
 1. A method of preparing a compound having formula(I):

or a salt thereof, wherein R¹ is Cl or CF₃; R² is F or Cl; and R³ is Hor CH₃; and wherein said compound of formula (I) is substantially freeof enantiomeric or diastereomeric impurities, said method comprising:(a) contacting a compound having the formula (i-3):

wherein R is selected from the group consisting of H, C₁₋₈ alkyl, aryland aryl-C₁₋₄ alkyl, which is substantially free of enantiomeric ordiastereomeric impurities, or a salt thereof, with a compound having theformula:

wherein LG is a leaving group; R² is F or Cl; and R³ is H or CH₃; underconditions sufficient to form a compound of formula (i-4):

and (b) contacting said compound of formula (i-4) with an aniline havingthe formula:

wherein R¹ is Cl or CF₃, in the presence of Al(Me)₃ to provide acompound of formula (I).
 2. The method of claim 1, wherein R¹ is CF₃, R²is F, and R³ is CH₃.
 3. The method of claim 1, wherein R¹ is CF₃, R² isCl, and R³ is H.
 4. The method of claim 1, wherein R¹ is Cl, R² is F,and R³ is CH₃.
 5. A method for the preparation of compounds of formula(I), or a pharmaceutically acceptable salt thereof, comprising: (a)reacting an ester of 3-(4-nitrophenyl)-3-oxo-propanoate (i-1) wherein Ris selected from the group consisting of C₁₋₈ alkyl, aryl and aryl-C₁₋₄alkyl, with (R)-(—)-2-phenylglycinol, and acrolein diethyl acetal, toproduce compound (i-2);

(b) hydrogenating or reducing (i-2) to produce an intermediate amine andconverting the intermediate amine to (i-3) with cyclopentanone and areducing agent;

(c) combining (i-3) with either 2-fluoro-6-methylbenzoyl chloride or2-chlorobenzoyl chloride in the presence of a first base to provide(i-4);

wherein R² is fluoro, R³ is methyl, and LG is chloro, or R² is chloro,R³ is hydrogen, and LG is chloro; (d) combining (i-4) with3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline in thepresence of Al(Me)3 to provide a compound of formula (I);

wherein, R¹ is Cl or CF₃.
 6. The method of claim 1, wherein LG isselected from the group consisting of halogen, hydroxyl,methanesulfonate (mesylate), trifluoromethanesulfonate (triflate),benzenesulfonate, 4-methylbenzenesulfonate(tosylate),4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, and thecarboxylate component of a mixed or symmetrical anhydride.
 7. The methodof claim 1, wherein LG is a halogen.
 8. The method of claim 1, whereinLG is Cl.
 9. The method of claim 1, wherein the contacting in step (a)is carried out in the presence of a base.
 10. The method of claim 9,wherein the base is selected from the group consisting of triethylamine,N,N-diisopropylethylamine, DBU, N-methyl morpholine, potassium carbonate(K₂CO₃), potassium bicarbonate (KHCO₃), sodium carbonate, and sodiumbicarbonate (NaHCO₃).